Tropomodulin (TMOD) is a protein which binds and caps the minus end of actin (the "pointed" end), regulating the length of actin filaments in muscle and non-muscle cells.[1]
The protein functions by physically blocking the spontaneous dissociation of ADP-bound actin monomers from the minus end of the actin fibre. This, along with plus end capping proteins, such as capZ stabilise the structure of the actin filament. End capping is particularly important when long-lived actin filaments are necessary, for example: in myofibrils. Inhibition of tropomodulin capping activity leads to dramatic increase in thin filament length from its pointed end.[2][3]
Actin filaments have two differing ends where one is the fast-acting barbed end and the other is the slow growing pointed end.[4] Since TMOD binds to the pointed end of actin it is essential in cell morphology, cell movement, and muscle contraction.[4] TMOD has been identified as an erythrocyte with 359 amino acids and it is a globular protein.[5] When tropomyosin is not present Tropomodulin also assists in partially inhibiting elongation and depolymerization at the pointed filament ends.[6] The N-terminal of Tropomodulin is rod shaped. This portion then binds to the N-terminal part of the two tropomyosin that are on the opposite part of the actin filaments in the muscle and nonmuscle cells.[7] TMOD is able to have high-affinity binding through low-affinity interactions because of its ability to control subunit exchange of the pointed end of the actin filaments.[5] When looking at epithelial cells Tropomodulin sustains F-actin in the lateral cell membranes and the adherens junction.[8] Tropomodulin binds exclusively to the pointed filament ends and not to actin monomers or alongside actin filaments.[9] Tropomodulin is a 40-kD tropomyosin-binding protein that was originally isolated from the red blood cell membrane skeleton.[6] Tropomodulin is associated with Leiomodin as homologous proteins because both proteins play a role in muscle sarcomere thin filament formation and maintenance.[7] An ortholog that is identified with TMOD and structurally similar is UNC-94. Where the UNC-94 protein is capping on the minus end of the actin filament. This protein like TMOD depends on the presence of tropomyosin in order to function properly.[7]
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How tropomyosin and troponin regulate muscle contraction | NCLEX-RN | Khan Academy
Transcription
In the last video, we learned how myosin-- and myosin II in particular-- when we say myosin II it actually has two of these myosin heads and their tails are inter-wound with each other-- how myosin II can use ATP to essentially-- you can almost imagine either pulling an actin filament or walking up an actin filament. It starts attached. ATP comes and bonds onto it. That causes it to be released. Then the ATP hydrolyzes into ADP and a phosphate group. And when that happens, that energy's released. It puts this into a higher energy state. It kind of spring-loads the protein and then it attaches up another notch on the actual actin filament and then the phosphate group leaves and that's where the confirmation change in this protein is enough. It generates the power stroke to actually push on the actin filament-- and you could imagine, either move the myosin-- whatever the myosin is connected to-- to the left or whatever the actin is connected to to the right. We're going to talk a lot more about what they're connected to in future videos. Now, a couple of questions might have been raising in your head. This guy had so much effort to pull on this thing, right? There's some tension pulling in the other direction, right? I said this is what happens in muscles, so there must be some weight or some other resistance. So what happens when this releases? At the first step when ATP joined and this released, wouldn't the actin filament just go back to where it was before? Especially if there's some tension on it going in that direction. And the simple answer to that is, this isn't the only myosin protein that's acting on this actin. You have others all along the chain. Maybe you have one right there. Maybe you have one right there. They're all working at their own pace at different times. So you have so many of these that when one of them is disengaged, another one of them might be in their power stroke or another one might be engaged. So it's not like you have this notion of, if all of a sudden one lets go, that the actin filament will recoil back to where it was. Now the next question that you might be thinking is, how do I turn on and off this situation? We have command over our muscles. What can turn on or off this system of the myosin essentially crawling up the actin? And to understand that, there's two other proteins that come into effect. That's tropomyosin and troponin. And so I'm going to redraw the actin-- I'll do a very rough drawing of the actin filament. Let's say that that's my actin filament right there with its little grooves. It's actually a helical structure. And actually, these grooves-- it's kind of a helical-- but we won't worry too much about that. What we drew so far, at least in the last video, you had these little myosin. You can view them as feet or head or whatever that keep attaching to it and then based on where they are in that ATP cycle, they can keep getting cranked back up or sprinr-loaded and go to the next one and push back. Now, on top of this actin, you actually have this tropomyosin protein. And this tropomyosin protein, it coils around the actin. So this is our actin right here. This is one of the two heads of the myosin II. And then we have our tropomyosin. Tropomyosin is coiled around. It's a very rough sketch, but you can imagine it's coiled around and it goes back behind it, then it goes like that, and then it goes back behind it, then it goes like that. So it's coiled around it and the important thing about it is, if there's-- let me take a step back. It's coiled around and it's attached to the actin by another protein called troponin. Let's say it's attached there and-- this isn't exact, but let's say it's attached there, and there, and there, and there, and there by the troponin. So let me write this down. So you can imagine, the troponin is kind of like the nails into the actin. So it dictates where the tropomyosin is. So when a muscle is not contracting, it turns out that the tropomyosin is blocking the myosin from being able to-- and I've read a bunch of accounts on this and I think this is still an area of research. It's not 100% clear one way or the other. Tropomyosin is-- or maybe both-- blocking the myosin from being able to attach to the actin where it normally attaches so it won't be able to crawl up the actin-- or sometimes the myosin is attached to the actin, but it keeps it from releasing and sliding up the actin to keep that walking procedure. So the bottom line is that this tropomyosin kind of blocks the myosin head-- this is the myosin head right there-- from crawling up the actin, either by physically blocking its actual binding site or if it's already bound, keeping it from being able to keep sliding up the actin. Either way, it's blocking it and the only way to make it unblocked is for the troponins to actually change their confirmation, for them to change their shape. And the only way for them to change their shape is if we have a high calcium ion concentration. So if you have a bunch of calcium ions, if you have a high enough concentration, these calcium ions are going to bond to the troponin and then that changes the confirmation of the troponin enough to move the configuration of the tropomyosin. So let me write this down. So normally, tropomyosin blocks, but then when you have a high calcium ion concentration, they bind to troponin and then the troponin, they change their confirmation so it moves the tropomyosin out of the way. So when it moves out of the way, you have a high calcium concentration, bonds troponin, moves tropomyosin out of the way, then all of a sudden what we talked about in the last video-- these guys can start walking up the actin or pushing the actin to the right, however you want to view it. But then if the calcium concentration goes low, then the calciums get released from the troponin. You need to have enough to always hang around here. If the concentration becomes really low here, these guys will start to leave. So then the troponin goes back to, I guess, standard confirmation. That makes the tropomyosin block the myosin again. So it's actually-- I mean, I can't say anything here is simple. This was only discovered maybe 50 or 60 years ago and you can imagine to actually observe these things or to create experiments to definitively know what's happening-- nothing is simple, but the idea is simple. Without calcium, the tropomyosin is blocking the ability of the myosin to attach where it needs to attach or slide up the actin so it can keep pushing on it. But if the calcium concentration is high enough, they will bond to the troponin-- which essentially nails down the tropomyosin that's wound around the actin and when they change their confirmation with the calcium ions, it moves the tropomyosin out of the way so that the myosin can do what it does. So you can imagine already, we're building up a way for-- one, for muscles to contract, but even better, for us to control muscles to contract. So if we have a high calcium concentration within the cell, the muscle will contract. If we have a low calcium concentration again, then all of a sudden, these will release. They'll be blocked, and then the muscle will relax again.
Genes
The TMOD genes are important for cell morphology, cell movement, and muscle contraction.[4] There are 4 identified Tropomodulin genes identified in humans: TMOD1, TMOD2, TMOD3, and TMOD4. The 4 identified genes are also recognized as Isoforms. There are also known orthologs of these isoforms in mice.[10] Known tropomodulin homologs have been identified in flies (Drosophila), worms (C.elegans), rats, chicks, and mice.[9][10] The TMOD genes are expressed at different levels in human tissue. The different levels can be identified as: the first level is heart and skeletal muscle, then the next level is found in brain, lung, and pancreas, then the last level in placenta, liver, and kidney.[5] Using the lab technique PCR TMOD gene was isolated and identified to have a total of 9 exons, allowing for the assumption that alternative promoters for tissue-specific expression and regulation.[5] TMOD1, TMOD3, and TMOD4 are the only isoforms that are found in muscles. TMOD2 is the only identified isoform that is only found in the brain and not in any muscles like the other isoforms. The two isoforms that are associated with neurons are TMOD1 and TMOD2.[7] The functions of each isoform can vary depending on the location of the Tropomyosin and actin filaments. Since the TMOD isoforms can influence stability of skeleton cells and regulate actin it can then be seen as essential for embryonic development.[7]
- TMOD1
- Tropomodulin 1 (TMOD1) can be found in various areas, but more specifically erythrocytes, the heart, and slow skeletal muscle. The structure for this protein varies slightly from the others where it has an N-terminus half and a C-Terminus half. The N-terminus half is seen to be mostly extended, unstructured, and flexible and the C-terminus half is seen to be compactly folded.[4] The inhibition of TMOD1 where an antibody inhibits the C-terminus or a decrease in the expression of TMOD1 can cause the c-terminal filaments to go from compactly folded to elongated and thin filaments. Thus causing there to be a decrease in the ability of the heart to be able to contract.[10] When looking at neurons TMOD1 is essential in synaptogenesis. TMOD1 is also important for spine morphogenesis and synapse formation where it can stabilize the F-actin.[8] In epithelial cells, such as ocular lens fiber cells, TMOD1 is important in maintaining the stability of the tropomyosin and F-actin so that the cells stay tightly packed and maintain the tissues mechanical integrity.[8]
- TMOD2
- Tropomodulin 2 (TMOD2) is an isoform that is more commonly found in the brain. TMOD2 like the other Tropomodulins is able to bind to the pointed end of actin and tropomyosin. In doing so TMOD2 is able to regulate actin nucleation and polymerization.[11] In regards to neurons TMOD 2 is essential in dendrite formation where it can regulate the branching of the dendrites.[8] When looking at the ortholog in mice, if there is a lack of the TMOD2 gene there will be a result of hyperactivity and impaired learning and memory.[8]
- TMOD3
TMOD3 visual - Tropomodulin 3 (TMOD3) is found to be essential in membranous skeleton and embryonic development.[12] TMOD3 is a wide ranging tropomodulin gene in non-erythroid cells, in which it regulates actin processes, such as lamellipodia protrusion and cell motility.[12] Lamellipodia protrusion, dense actin filaments, are usually found in neurons and epithelial cells where TMOD3 is mostly found. Change in regulation and reduction can drastically change the function of neurons or epithelial cells. We also find the gene TMOD 3 in polarized epithelial cell plasma membranes and the sarcoplasmic reticulum membranes of skeletal muscle.[13] This TMOD is the only isoform of the 4 known to be found in the human platelet proteome.[13] The way that TMOD3 functions in actin membranous skeleton structures is by capping the F-actin in stress fibers. If TMOD3 is not present there will be impaired erythroblast maturation in definitive erythropoiesis.[8] TMOD3 actin binding is regulated via phosphatidylinositol 3-kinase (PI3K)–Akt signaling in adipocytes, where Tmod3 regulation of cortical actin assembly with Tropomyosin. The regulation of TMOD3 is essential for insulin-mediated trafficking of the glucose transporter Glut4 to the plasma membrane.[8] In intestinal epithelial cells if there is a reduction in TMOD3 the binding of tropomyosin and F-actin will be disrupted and cause the cell height to collapse.[8] This collapse in cell height can change the overall functionality of the intestinal cells.
- TMOD4
References
- ^ Rao JN, Madasu Y, Dominguez R (July 2014). "Mechanism of actin filament pointed-end capping by tropomodulin". Science. 345 (6195): 463–467. Bibcode:2014Sci...345..463R. doi:10.1126/science.1256159. PMC 4367809. PMID 25061212.
- ^ Gregorio CC, Weber A, Bondad M, Pennise CR, Fowler VM (September 1995). "Requirement of pointed-end capping by tropomodulin to maintain actin filament length in embryonic chick cardiac myocytes". Nature. 377 (6544): 83–86. Bibcode:1995Natur.377...83G. doi:10.1038/377083a0. PMID 7544875. S2CID 4279512.
- ^ Gunning PW, Ghoshdastider U, Whitaker S, Popp D, Robinson RC (June 2015). "The evolution of compositionally and functionally distinct actin filaments". Journal of Cell Science. 128 (11): 2009–2019. doi:10.1242/jcs.165563. PMID 25788699.
- ^ a b c d Kostyukova AS, Choy A, Rapp BA (October 2006). "Tropomodulin binds two tropomyosins: a novel model for actin filament capping". Biochemistry. 45 (39): 12068–12075. doi:10.1021/bi060899i. PMC 2596622. PMID 17002306.
- ^ a b c d "Entry - *190930 - TROPOMODULIN 1; TMOD1 - OMIM". www.omim.org. Retrieved 2023-11-28.
- ^ a b Weber A, Pennise CR, Babcock GG, Fowler VM (December 1994). "Tropomodulin caps the pointed ends of actin filaments". The Journal of Cell Biology. 127 (6 Pt 1): 1627–35. doi:10.1083/jcb.127.6.1627. PMC 2120308. PMID 7798317.
- ^ a b c d e "Tropomodulin - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2023-11-28.
- ^ a b c d e f g h i j "Tropomodulins".
- ^ a b Weber A, Pennise CR, Fowler VM (December 1999). "Tropomodulin increases the critical concentration of barbed end-capped actin filaments by converting ADP.P(i)-actin to ADP-actin at all pointed filament ends". The Journal of Biological Chemistry. 274 (49): 34637–45. doi:10.1074/jbc.274.49.34637. PMID 10574928.
- ^ a b c Cox PR, Siddique T, Zoghbi HY (2001-10-17). "Genomic organization of Tropomodulins 2 and 4 and unusual intergenic and intraexonic splicing of YL-1 and Tropomodulin 4". BMC Genomics. 2 (1): 7. doi:10.1186/1471-2164-2-7. PMC 59888. PMID 11716785.
- ^ Kuruba B, Starks N, Josten MR, Naveh O, Wayman G, Mikhaylova M, Kostyukova AS (August 2023). "Effects of Tropomodulin 2 on Dendritic Spine Reorganization and Dynamics". Biomolecules. 13 (8): 1237. doi:10.3390/biom13081237. PMC 10515316. PMID 37627302.
- ^ a b Jin C, Chen Z, Shi W, Lian Q (May 2019). "Tropomodulin 3 promotes liver cancer progression by activating the MAPK/ERK signaling pathway". Oncology Reports. 41 (5): 3060–3068. doi:10.3892/or.2019.7052. PMID 30864730. S2CID 76665802.
- ^ a b Sui Z, Nowak RB, Sanada C, Halene S, Krause DS, Fowler VM (July 2015). "Regulation of actin polymerization by tropomodulin-3 controls megakaryocyte actin organization and platelet biogenesis". Blood. 126 (4): 520–530. doi:10.1182/blood-2014-09-601484. PMC 4513252. PMID 25964668.
External links
- Tropomodulin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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This page was last edited on 12 May 2024, at 18:02